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gleevec metabolism

Gábor Somlyai, T Que Collins, Emmanuelle J Meuillet, Patel Hitendra, Dominic P D'Agostino, László G Boros
Phenformin's recently demonstrated efficacy in melanoma and Gleevec's demonstrated anti-proliferative action in chronic myeloid leukemia may lie within these drugs' significant pharmacokinetics, pharmacodynamics and structural homologies, which are reviewed herein. Gleevec's success in turning a fatal leukemia into a manageable chronic disease has been trumpeted in medical, economic, political and social circles because it is considered the first successful targeted therapy. Investments have been immense in omics analyses and while in some cases they greatly helped the management of patients, in others targeted therapies failed to achieve clinically stable recurrence-free disease course or to substantially extend survival...
July 25, 2017: Oncotarget
William J Netzer, Karima Bettayeb, Subhash C Sinha, Marc Flajolet, Paul Greengard, Victor Bustos
Neurotoxic amyloid-β peptides (Aβ) are major drivers of Alzheimer's disease (AD) and are formed by sequential cleavage of the amyloid precursor protein (APP) by β-secretase (BACE) and γ-secretase. Our previous study showed that the anticancer drug Gleevec lowers Aβ levels through indirect inhibition of γ-secretase activity. Here we report that Gleevec also achieves its Aβ-lowering effects through an additional cellular mechanism. It renders APP less susceptible to proteolysis by BACE without inhibiting BACE enzymatic activity or the processing of other BACE substrates...
February 7, 2017: Proceedings of the National Academy of Sciences of the United States of America
Soo-Youl Kim
Drug development groups are close to discovering another pot of gold-a therapeutic target-similar to the success of imatinib (Gleevec) in the field of cancer biology. Modern molecular biology has improved cancer therapy through the identification of more pharmaceutically viable targets, and yet major problems and risks associated with late-phase cancer therapy remain. Presently, a growing number of reports have initiated a discussion about the benefits of metabolic regulation in cancers. The Warburg effect, a great discovery approximately 70 years ago, addresses the "universality" of cancer characteristics...
March 2015: Biomolecules & Therapeutics
Nicole A Doudican, Ansu Kumar, Neeraj Kumar Singh, Prashant R Nair, Deepak A Lala, Kabya Basu, Anay A Talawdekar, Zeba Sultana, Krishna Kumar Tiwari, Anuj Tyagi, Taher Abbasi, Shireen Vali, Ravi Vij, Mark Fiala, Justin King, MaryAnn Perle, Amitabha Mazumder
BACKGROUND: The personalization of cancer treatments implies the reconsideration of a one-size-fits-all paradigm. This move has spawned increased use of next generation sequencing to understand mutations and copy number aberrations in cancer cells. Initial personalization successes have been primarily driven by drugs targeting one patient-specific oncogene (e.g., Gleevec, Xalkori, Herceptin). Unfortunately, most cancers include a multitude of aberrations, and the overall impact on cancer signaling and metabolic networks cannot be easily nullified by a single drug...
2015: Journal of Translational Medicine
George C Prendergast, Courtney Smith, Sunil Thomas, Laura Mandik-Nayak, Lisa Laury-Kleintop, Richard Metz, Alexander J Muller
Genetic and pharmacological studies of indoleamine 2,3-dioxygenase (IDO) have established this tryptophan catabolic enzyme as a central driver of malignant development and progression. IDO acts in tumor, stromal and immune cells to support pathogenic inflammatory processes that engender immune tolerance to tumor antigens. The multifaceted effects of IDO activation in cancer include the suppression of T and NK cells, the generation and activation of T regulatory cells and myeloid-derived suppressor cells, and the promotion of tumor angiogenesis...
July 2014: Cancer Immunology, Immunotherapy: CII
Saranya Kittanakom, Anthony Arnoldo, Kevin R Brown, Iain Wallace, Tada Kunavisarut, Dax Torti, Lawrence E Heisler, Anuradha Surendra, Jason Moffat, Guri Giaever, Corey Nislow
The application of new proteomics and genomics technologies support a view in which few drugs act solely by inhibiting a single cellular target. Indeed, drug activity is modulated by complex, often incompletely understood cellular mechanisms. Therefore, efforts to decipher mode of action through genetic perturbation such as RNAi typically yields "hits" that fall into several categories. Of particular interest to the present study, we aimed to characterize secondary activities of drugs on cells. Inhibiting a known target can result in clinically relevant synthetic phenotypes...
August 2013: G3: Genes—Genomes—Genetics
Monique Hinchcliff, Chiang-Ching Huang, Wataru Ishida, Feng Fang, Jungwha Lee, Nadareh Jafari, Mark Wilkes, Swati Bhattacharyya, Edward Leof, John Varga
OBJECTIVES: Systemic sclerosis (SSc) is a heterogeneous multifactorial disease dominated by progressive skin and internal organ fibrosis that is driven in part by transforming growth factor-beta (TGF-β). An important downstream target of TGF-β is the Abelson (c-Abl) tyrosine kinase, and its inhibition by imatinib mesylate (Gleevec) attenuates fibrosis in mice. Here we examined the effect of c-Abl activation and blockade in explanted healthy control and SSc fibroblasts. METHODS: Skin biopsies and explanted fibroblasts from healthy subjects and patients with SSc were studied...
March 2012: Clinical and Experimental Rheumatology
John A Lowe, Phil Jones, David M Wilson
The decline in productivity of the pharmaceutical industry may stem, at least in part, from underestimating the complexity of human disease. While a disease-relevant gene or protein may initially seem to be an attractive drug target, appreciating its role in the network of pathways involved in a disease provides a better perspective for making this decision. In some cases, off-target effects or redundancy in the network can negate the potential efficacy of a new drug. Even a successful drug, such as imatinib (Gleevec), may be less selective than originally thought, resulting in important, and sometimes useful, consequences...
September 2010: Current Opinion in Drug Discovery & Development
Mark E Burkard, Prasad V Jallepalli
Targeted therapies for cancer promise to revolutionize treatment by specifically inactivating pathways needed for the growth of tumor cells. The most prominent example of such therapy is imatinib (Gleevec), which targets the BCR-ABL kinase and provides an effective low-toxicity treatment for chronic myelogenous leukemia. This success has spawned myriad efforts to develop similarly targeted drugs for other cancers. Unfortunately, the high expectations of these efforts have not yet been realized, likely due to the genetic diversity among and within tumors, as well as the complex and largely unpredictable interactions of drug-like compounds with innumerable targets that affect cellular and organismal metabolism...
December 2010: Biochimica et Biophysica Acta
Stefan Duensing, Anette Duensing
Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the gastrointestinal (GI) tract and are caused by activating KIT or PDGFRA mutations. GISTs can be successfully treated with the small molecule kinase inhibitor imatinib mesylate (Gleevec, Novartis) with response rates of up to 85%. However, complete responses are rare, and most patients will develop imatinib resistance over time. Recent results have shown that although imatinib effectively stimulates apoptotic cell death in sensitive GIST cells, a considerable proportion of cells does not undergo apoptosis, but instead enters a state of quiescence...
September 1, 2010: Biochemical Pharmacology
Russell T Turner, Urszula T Iwaniec, Kevin Marley, Jean D Sibonga
Chronic hyperparathyroidism (HPT) is a common cause of metabolic bone disease. These studies investigated the underlying cellular and molecular mechanisms responsible for the detrimental actions of elevated parathyroid hormone (PTH) on the skeleton. Bone biopsies from hyperparathyroid patients revealed an association between parathyroid bone disease and increased numbers of bone marrow mast cells. We therefore evaluated the role of mast cells in the etiology of parathyroid bone disease in a rat model for chronic HPT...
July 2010: Journal of Bone and Mineral Research: the Official Journal of the American Society for Bone and Mineral Research
Warner K Huh, Michael W Sill, Kathleen M Darcy, Kevin M Elias, James S Hoffman, John F Boggess, Ronald D Alvarez, Harry J Long, David M O'Malley, Michael J Birrer
PURPOSE: This multi-institutional phase II trial assessed the activity and toxicity of imatinib mesylate and explored c-Kit and platelet-derived growth factor receptor (PDGFR)-beta in recurrent or persistent uterine carcinosarcoma. METHODS: Women with measurable uterine carcinosarcoma, who had a performance status of 0, 1, or 2 and had received up to two prior treatment regimens, were eligible and treated with a 600-mg daily oral dose of imatinib mesylate until disease progression or unacceptable toxicity...
May 2010: Gynecologic Oncology
Fengjia Zhu, Yi Wang, Su Zeng, Xiaoyun Fu, Linbo Wang, Jiang Cao
Multidrug resistance (MDR) to chemotherapy is a significant barrier to the effective treatment of chromic myeloid leukemia (CML). In an attempt to identify more factors associated with MDR for an understanding of the mechanism, we first established an adriamycin (ADR)-resistant human erythroleukemia cell line K562/ADR by stepwise selection in vitro using ADR. Besides the elevated resistance to ADR, the K562/ADR cells also showed significantly increased crossed-resistance to vincristin and Gleevec, compared to the parental K562 cells...
December 2009: Omics: a Journal of Integrative Biology
Seppo Parkkila, Alessio Innocenti, Heini Kallio, Mika Hilvo, Andrea Scozzafava, Claudiu T Supuran
The protein tyrosine kinases (PTKs) are essential enzymes in cellular signaling processes that regulate cell growth, differentiation, migration and metabolism. Their inhibition was recently shown to constitute a new modality for treating cancers. Two clinically used PTK inhibitors (PTKIs), imatinib (Glivec/Gleevec) and nilotinib (Tasigna) were investigated for their effects on the zinc enzymes carbonic anhydrases (CAs, EC The two PTKIs inhibited all 13 catalytically active mammalian isoforms CA I-XV with K(I)s in the range of 4...
August 1, 2009: Bioorganic & Medicinal Chemistry Letters
Bhavinkumar B Patel, Yin A He, Xin-Ming Li, Andrey Frolov, Lisa Vanderveer, Carolyn Slater, Russell J Schilder, Margaret von Mehren, Andrew K Godwin, Anthony T Yeung
BACKGROUND: Imatinib mesylate (Gleevec, Novartis, Basel, Switzerland) is a small-molecule tyrosine kinase inhibitor with activity against ABL, BCR-ABL, c-KIT, and PDGFR alpha. Several clinical trials have evaluated the efficacy and safety of imatinib in patients with ovarian carcinoma who have persistent or recurrent disease following front-line platinum/taxane based chemotherapy. However, there is limited pre-clinical and clinical data on the molecular targets and action of imatinib in ovarian cancer...
May 2008: Cancer Genomics & Proteomics
L G Boros, T F Boros
The metabolic phenotype of tumor cells promote the proliferative state, which indicates that (a) cell transformation is associated with the activation of specific metabolic substrate channels toward nucleic acid synthesis and (b) increased expression phosphorylation, allosteric or transcriptional regulation of intermediary metabolic enzymes and their substrate availability together mediate unlimited growth. It is evident that cell transformation due to various K-ras point mutations is associated with the activation of specific metabolic substrate channels that increase glucose channeling toward nucleic acid synthesis...
2007: Ernst Schering Foundation Symposium Proceedings
Mehmet Emin Kalender, Alper Sevinc, Mustafa Yilmaz, Coskun Ozsarac, Celalettin Camci
Malignant mesenchymal tumors consist of approximately 10% of uterine tumors. The majority of uterine sarcomas are leiomyosarcoma and endometrial stromal sarcoma (ESS). Surgery, radiotherapy, chemotherapy, and hormonal therapy are used for the treatment of ESS. Imatinib mesylate is indicated in the management of gastrointestinal stromal tumor and chronic myelogeneus leukemia. There is an interest to use imatinib mesylate in the treatment of c-kit positive ESS. We reported a case of 42-year-old female low-grade ESS progressed on chemotherapy and presented with objective response to imatinib mesylate...
February 2009: Cancer Chemotherapy and Pharmacology
Margret S Rodrigues, Mamatha M Reddy, Martin Sattler
Neoplastic expansion of myeloid cells is associated with specific genetic changes that lead to chronic activation of signaling pathways, as well as altered metabolism. It has become increasingly evident that transformation relies on the interdependency of both events. Among the various genetic changes, the oncogenic BCR-ABL tyrosine kinase in patients with Philadelphia chromosome positive chronic myeloid leukemia (CML) has been a focus of extensive research. Transformation by this oncogene is associated with elevated levels of intracellular reactive oxygen species (ROS)...
October 2008: Antioxidants & Redox Signaling
Lisa J Christopher, Donghui Cui, Chiyuan Wu, Roger Luo, James A Manning, Samuel J Bonacorsi, Michael Lago, Alban Allentoff, Francis Y F Lee, Betty McCann, Susan Galbraith, Donald P Reitberg, Kan He, Anthony Barros, Anne Blackwood-Chirchir, W Griffith Humphreys, Ramaswamy A Iyer
SPRYCEL (dasatinib, BMS-354825; Bristol-Myers Squibb, Princeton, NJ), a multiple kinase inhibitor, is currently approved to treat chronic myelogenous leukemia and Philadelphia chromosome-positive acute lymphoblastic leukemia tumors in patients who are resistant or intolerant to imatinib mesylate (Gleevec; Novartis, Basel, Switzerland). After a 100-mg single p.o. dose of [(14)C]dasatinib to healthy volunteers, the radioactivity was rapidly absorbed (T(max) approximately 0.5 h). Both dasatinib and total radioactivity (TRA) plasma concentrations decreased rapidly with elimination half-life values of <4 h...
July 2008: Drug Metabolism and Disposition: the Biological Fate of Chemicals
Elizabeth M Pinder, Gurprit S S Atwal, Abraham A Ayantunde, Sarah Khan, Mike Sokal, Tom McCulloch, Simon L Parsons
Tumour lysis syndrome (TLS) is a rare side effect of chemotherapy for solid tumours. It describes the metabolic derangements following rapid and extensive tumour cell death following a good response to chemotherapy. Symptoms are those of metabolic derangement and renal failure. Treatment involves rehydration and correction of metabolic abnormalities. TLS should be considered in high risk groups. We report a case of TLS in a patient with metastatic gastrointestinal stromal tumour treated with imatinib mesylate...
2007: Sarcoma
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